Process of preparing 2, 3-seco-3-oxo-20alpha-yohimbane compounds and products obtained thereby



United States Patent 2,988,552 PROCESS OF PREPARING 2, 3-SEC0-3-0X0-20a-YOI-HMBANE COMPOUNDS A'ND PROD- UCTS OBTAINED THEREBY Jean Jolly,Fonteuay-sous-Bois, and Robert Joly, Montmoreucy, France, assignors toLes Laboratoires Frangais dc Chimiotherapie, Paris, France, acorporation of France No Drawing. Filed July 30, 1958, Ser. No. 751,872Claims priority, application France Aug. 9, 1957 7 Claims. (Cl. 260-287)The present invention relates to a process of preparing2,3-seco-3-oxo-20a-yohimbane compounds and more particularly to animproved cyclization process, and to products obtained thereby.

2,3-seco-3-oxo-20u-yohimbane compounds have been prepared heretofore bycondensing the methyl ester of lfi-carboxy methyl-2fl-methoxycarbonyl-3a-methoxy-4flacetoxy-6B-formyl cyclohexane with a tryptaminecompound and subjecting the resulting Schiif base to simultaneousredu'ction and cyclization. This process has the great disadvantage thatthe preparation of the starting material, i.e. the methyl ester of1,8-car-boxy methyl-2,6- metihoxycarbonyl-3oc-methoxy-4fl-acetoxy=6p-formyl cyclohexane is ratherdifiicult. This compound is prepared by esterification of llioarboxymethyl-2fimethoxy carbonyl-3a-methoxy-4 3-acetoxy- 6 8-formylcyclohexane of Formula I given hereinafter, by means of diazomethane.Through the last mentioned cyclohexane compound can be readily producedon an industrial scale, the diazomethane esterification is a cumbersomeoperation. Furthermore, reductive cyclization of the Schiif baseaccording to the processes heretofore known does not proceedquantitatively.

It is therefore one object of the present invention to provide a simpleand efiective process of producing 2,3- seco-3-oxo-20a-yohimbanecompounds which are useful as intermediates in the preparation ofcompounds of the reserpine series. 7

Another object of the present invention is to provide new and valuableintermediates obtained in the course of said process.

These and other objects of the present invention and advantageousfeatures thereof will become apparent as the description proceeds.

In principle, the present invention involves the preparation of2,3-seco-3-oxo-20a-yohimbane compounds of the general Formula V f 0 R HI CHaOOU O-OOGH3 wherein R R R and R indicate hydrogen, halogen,especially !chlorine and bromine, a lower alkoxy group, the hydroxylgroup, or a lower alkyl radical. Said substituents may be different fromeach other or they may be alike and the benzene ring may be mono, di-,or, respectively, tri-substituted.

According to the present invention said 2,3-seco-3-oxo- Not-yohimbanecompounds are prepared by condensing a salt of lfi-carboxymethylZpmethoxy carbonyl-3aice methoxy-4fl-acetoxy-6B-formyl cyclohexane ofFormula I with an organic or inorganic base, such as the trietlhylaminesalt or the sodium or potassium salt of said acid With the desiredtryptamine compound of Formula II, to yield the corresponding salt ofthe Schifi base of Formula III. Said salt of the Schilf base of FormulaIII, ie the salt of 18fl-acetoxy-17a-methoxy-16fl-methoxy carbonyl 2,33,4 diseco A 20oz yohimbene- 3-oic acid is hydrogenated at a lowtemperature whereby the double bond is saturated and the compound ofFormula IV, i.e. 18B-acetoxy-17oc-methoxy-l6;B-methoxycarbonyl-2,3-3,4-diseco-20a-yohimbane-3-oi'c acid is obtained. Whenheating said saturated yohimbane compound of Formula IV at a temperaturebetween about C. and its melting point and preferably at a temperatureof about 0., water is split off and cyclization takes places. Thereby,the lactam compound of Formula V, i.e.ISB-acetoxy-17u-methoxy-165-methoxy carbonyl-2,3-seco-3-oxo-2 0uyohimbane, is obtained in a high yield.

The carboxylic acid compound of Formula I can readily be prepared on anindustrial scale according to the process described in commonly assignedapplications Serial No. 693,028, filed October 29, 1957, now Patent No.2,952,682, and entitled Polycyclic Compounds and Process of PreparingSame, and copending Serial No. 727,780, filed April 9, 1958, andentitled Process of Producing a Substituted Aldehyde, by ozoru'zing themethyl ester of 3 3-acetoxy-2a-methoxy-7-oxo1,2,3,4, 4au,7,8,8aaoctahydronaphthalene 1B carboxylic acid and decomposing the resultingozonide at a low temperature.

The process according to the present invention considerably simplifiesthe preparation of reserpine compounds on an industrial scale becausethe use of diazomethane which is an expensive, highly toxic reagentdiflicult to handle on large scale operation, is avoided. Furthermore,the yield of the lactam lcompound of Formula V is considerably higherthan heretofore attainable.

The following examples serve to illustrate the present inventionwithout, however, limiting the same thereto. More particularly, otherinorganic or organic basic compounds than those mentioned hereinabovemay be used for preparing the salts of the compound of Formula IV; thereaction temperature may be varied; other tryptamine compounds may beused for the preparation of the Schiff base of Formula III, forinstance, 5-chloro-6-methoxy tryptamine, 6-chloro tryptamine, S-methoxytryptamine, S-chloro tryptamine, 7-methoxy tryptamine, 7-chlorotryptamine and others; and the ra'cemic mixtures of the aldehyde ofFormula I may be employed as starting material in accordance with theprinciples set forth herein and in the claims annexed hereto.

The reaction according to the present invention is furthen-moreillustrated by the reaction diagram on the following formula sheet.

The melting points are instantaneous melting points determined on theMaquenne block.

EXAMPLE 1 Preparation of the triethylamine salt of IB-carboxy methyl 2,3methoxy carbonyl 3a methoxy 4B acetoxy- 6f3-formyl cyclohexane (FormulaI) 5 g. of the compound of Formula I, having a rotary power of [a] =+142(in pyridine, concentration: 1%) are added to 50 cc. of water whilestirring and passing nitrogen through the suspension and cooling thesame to a temperature between C. and C. 2.6 cc. of triethylamine(corresponding to an excess of 20%) are added to said suspension. Aclear solution of the desired salt is obtained which can directly beused for further reaction.

EXAMPLE 2 Preparation of the triethylamine salt of 18B-acet0xy- 11,17a-dimethoxy-16/3-methoxy carbonyl-2,3-3,4-diseco 15-20a-yohimbene-3-oic acid (Formula III wherein R =OCH R R R =H) 3.3 g.of 6-methoxy tryptamine (Formula 11, wherein 4 R =OCH R R R =H) areadded within about two minutes to the solution of the triethylamine saltof the compound of Formula I prepared according to Example 1 whilekeeping the solution at a temperature between 0 and +5 C., stirring, andbubbling nitrogen therethrough. After minutes, a yellow clear solutionof the desired salt is obtained.

EXAMPLE 3 Preparation of 18B-acetoxy-1L1 7a-dimethoxy-1 6,8-methoxycarbony[-2,3-3,4-diseco-20a-yohimbane-3-0ic acid (Formula IV, wherein R=OCH R R R =H) 0.75 g. of potassium boronhydride are added in smallportions and very slowly to the solution of the salt of the Schifi baseof Formula III, obtained according to Example 2. After standing for 15minutes at +5 C., the temperature is allowed to rise to 15-20 C. 5 cc.of methanol are added and the solution is slowly acidified to a pH of5-6 by the addition of about 18% hydrochloric acid. The acid compound ofFormula IV crystallizes. After standing at +5 C. for 30 minutes, thecrystals are filtered oil with suction and washed with water. Afterdrying 6.45 g. (83% of the theoretical yield) of the desired carboxylicacid of Formula IV are obtained. The compound has a rotary power of [a]=39 (concentration: 0.5% in pyridine). It does not melt but it sinterswhen heated on the block at 140145 C. and is dehydrated at about 150 C.whereby the lactam compound of Formula V is formed.

Analysis.C H O N =490.54. Calculated: 61.21% C; 6.98% H; 26.09% 0; 5.71%N. Found: 61.3% C; 6.9% H; 26.1% 0; 5.8% N.

Acid number.-Calculated: 114. Found: 113.

The carboxylic acid of Formula 1V behaves as an amino acid. It issoluble in dilute alkali hydroxide solutions as well as in dilute acids.

The compound has not yet been described in the literature.

When using the equivalent amount of potassium bicarbonate or sodiumbicarbonate, in place of triethylamine as it is employed in thepreceding examples, the

same product is obtained. Thereby, first the potassium or sodium saltsof the compounds of Formulas I and III are formed which are convertedinto the 3-oic acid of Formula IV by following the procedure of thepreceding examples.

EXAMPLE 4 Preparation of 18fl-acet0xy-I1,17a-dimethoxy-16B-methoxycarbonyl-2,3-seco-3-oxo-20a-yohimbane (Formula V, wherein R =OOH R R R=H) 3 g. of the carboxylic acid of Formula IV, prepared according toExample 3 are dissolved in 3 cc. of cold dimethyl formamide and thesolution is heated at C. for 5-7 minutes. After cooling to 15-20" C. thesolution is poured in 30 cc. of ice water and the mixture is stirred for30 minutes. The precipitated crystals are filtered oil with suction,washed with water, and dried at 80 C. The desired 189-acetoxy-11,17oc-dimethoxy-16fi-methoxycarbonyl-2-3-seco-3-oxo-20a-yohimbane of Formula V is obtained in ayield of 96% of the theoretical amount. It melts at 162 C., thensolidifies, and melts again at 184 C. It has a rotatory power of [u]=+31+B (concentration: 0.5% in ethanol).

Acid namber.Calculated: 237. Found: 231.5.

EXAMPLE 5 (Formula II], wherein R R R R =H) On proceeding according toExample 2, using the solution of the triethylamine salt of thecarboxylic acid of Formula I, corresponding to 5 g. of said acid, and

obtained.

EXAMPLE 6 Preparation of 18 3-acet0xy-17oc-methoxy-16fi-methoxycarbonyl-2,3-3,4-diseco-20a-y0himbane-3-0ic acid (Formula IV, wherein RR R R =H) The solution obtained according to Example 5 is treated byfollowing the procedure described in Example 3.

The resulting carboxylic acid of Formula IV has a rotatory power of [a]=-35.5 (concentration: 0.5% in pyridine). It contains half a mole ofwater of crystallization. The compound does not melt but sinters whenheated on the block and is dehydrated at about 150 C. whereby thelactarn corresponding to Formula V is obtained.

Analysis.C H O ,-N +%H O=469.52. Calculated (with /2 mole of water):61.38% :C; 7.08% H; 25.56% 5.97% Found: 61.48% C; 7.02% H; 25.8% 0; 5.9%N.

The compound has not yet been described in the literature.

EXAMPLE 7 Preparation of 18,8-acetoxy-17a-meth0xy-16;3-methoxycarb0nyl-2,3-sec0-3-0x0-20a-yohimbane (Formula V, wherein R R R R =H)withthere is obtained the compound of Formula III whereinfi-methoxytryptamino R2=OOHB; R1, R R =H 7-methoxy tryptamine R4=OOHa; R1, R2,R3=H 4,5,6-trimethoxy tryptamine R1, R2, R3=OCH3; R4=H 5-cl1l0rotryptamine R2=C1; R1, R3, R4=H B-chloro tryptamine- R3=C1; R R2, R4=H7-chloro tryptamine.. R4=Cl; R1, R1, R =H 4,7 dichloro tryptamm R1,R4=Cl; R2, R3=H 6,7 dichloro tryptamme- Ra, R4=C1; R1, R2=Hi-chloro-7-methoxy tryptamme E-chloro-fi-methoxy tryptamine6-ol1l0ro-7-mothoxy tryptamine 7-chl0ro-6-methoxy tryptamine fi-methyltryptaminc Y-methyl tryptamine Conversion of the salts of the resultingcompounds of Formula III, as they can be obtained with the abovementioned and other substituted tryptamine compounds, into thecorresponding saturated 18fi-acetoxy-17a-methoXy-16fl-methoxycarbonyl-2,3-3,4-diseco-20a-yohirnbane- 3-oic acid compounds of FormulaIV is efiected by reduction with potassium boronhydride and into thecorresponding 18,8-acetoxy-l7a-methoxy-16fl-methoxycarbonyl-2,3-seco3-oxo-20ayohimbane compound 0t Formula V by heating toabout 150 C. as described in the preceding examples. Further conversionof the compounds of Formula V into reserpine-like compounds is carriedout, for instance, as described in the above mentioned 6 copendingapplications and in copending commonly assigned application Serial No.727,777.

We claim: 1. The process of preparing a 2,3-seco-3-oxo-20ayohimbanecompound of the formula wherein R R R and R represent members selectedfrom the group consisting of hydrogen, chlorine, methoXy and methylwhich comprises the steps or tornring a Water-soluble salt of lp-carboxymethyl-Z/i-methoxy carbonyl-3a methoxy-4fi-acetoxy 6p iormyl-cyclohexanein water, adding a tryptamine compound of the formula N u NH R H /C HO H,I u H CHaOC OCOCH3 CCHs wherein R R R and R have the meanings aboveassigned, heating said acid to a temperature between about C. and itsmelting point to cause cyclization and recovering said2,3-seco-3-oxo-20a-yohimbane compound.

2. The process of preparing 18,8-acet0xy-1Ll7a-dimethoxy 465- methoxycarbonyl -2,3- seco -3- OXO-ZOuyohimbane which comprises the steps offorming a watersoluble salt of 1fi-carboxy methyl-Zfi-methoxy carbonyl-3a-methoXy-4;3-acetoxy-6B-formyl-cyclohexane in water, adding6-methoXy-tryptamine, adding an alkali metal boronhydride to theresulting Schifi base at a temperature between 0 C. and room temperatureto cause hydrogenation of the N=C double bond, neutralizing theresulting solution With an acid, separating the l8 3-acetoxy- 11,1711dimethoxy 16,8 methoxy carbonyl 2,3-3,4- diseco-ZOwyohimbane-Z:-oicacid, heating said acid to a temperature between about 100 C. and itsmelting point to cause cyclization and recovering said 2,3-seco-3-0Xo-20u-yohimbane compound.

3. The process of preparing ISB-acetoxy-Ua-methoxy- 16B methoxy carbonyl2,3 se'co 3 oxo 20ozyohimbane which comprises the steps of forming awatersoluble salt of lp-carboxy methyl-Zfl-methoxy carbonyl-3a-methoxy-4p-acetoxy-fifl-formyl-cyclohexane in water, addingtryptamine, adding an alkali metal boronhydride to the resulting Schiffbase at a temperature between 0 C. and room temperature to causehydrogenation of the N=C double bond, neutralizing the resultingsolution with an acid, separating the 18/3-acetoxy-17a-methoxy- 163-methoxy carbonyl -2,3-3,4- diseco -20ayohimbane- 3-oic acid, heatingsaid acid to a temperature between about 100 C. and its melting point tocause cyclization and recovering said 2,3-seco-3-oxo-20a-yohimbanecompound.

4. The process according to claim 1, wherein the said soluble salt oflfi-carboxy methyl-Zfl-methoxy carbonyl- 3a-rnethoxy4p-acetoxy-6fi-formyl cyclohexane is a salt selected from the groupconsisting of the potassium salt, the sodium salt, and the triethylaminesalt.

5. The process according to claim 1, wherein the alkali metalboronhydride is a compound selected from the group consisting ofpotassium boronhydride and sodium boronhydride.

6. The proocess according to claim 1, wherein cycli- Zation is carriedout at about 150 C.

7. The procws according to claim 1, wherein cyclization is carried outin dimethyl formamide.

References Cited in the file of this patent UNITED STATES PATENTS KuehneOct. 21, 1958 Woodward Apr. 21, 1959 OTHER REFERENCES

1. THE PROCESS OF PREPARING A 2,3-SECO-3-OXO-20AYOHIMBANE COMPOUND OFTHE FORMULA